Effect of Maternal Diabetes on Pre- and Post-Natal Redox Status of F1 Rat Offspring

Abstract

Background: The oxidative stress and disturbed redox signaling during gestation my play an important role in the fetal programming of adult diabetes. Objective: The study aimed to investigate the effects of maternal diabetes on pre-and post-natal pancreatic and peripheral tissues redox and oxidative status in order to clarify their role in the diabetogenic programming of F1 offspring. Methods: Two groups of female Wistar rats were used (diabetic and control); diabetes was neonatally induced by STZ injection to 5-day old rats. 10 pregnancies of each group were terminated at GD 17 to obtain placentas and fetal pancreas, liver, muscle and adipose tissues for prenatal measurements. The rest of pregnancies were completed to term and the offspring were weaned to control diet or high-caloric (HCD) diet and followed up for 30 weeks. Every 5 weeks 10 male rats were sacrificed and serum and tissues were obtained for assessment of fasting blood glucose, tissues content of 8-oxo-dG, TBARS, GSH, GSSG, antioxidant enzymes and caspase-3. Results: The results indicated that, prenatally redox status of the foetuses of diabetic mothers is shifted toward more oxidizing environment which results from elevated oxidative stress and impaired antioxidants as indicated by elevated fetal tissues content of 8-oxo-dG, TBARS and GSSG and decreased GSH and GSH/GSSG ratio. All of these induce the apoptotic pathway in fetal pancreas. Postnatally, impaired glucose tolerance in the offspring of diabetic mothers is detected at 15 th week of age and no hyperglycemia was detected until age of 30 weeks in the offspring under CD while some of offspring under HCD at age 25 weeks and most of them at 30 weeks have developed hyperglycemia. The pancreas of the offspring of diabetic mothers suffers from oxidative stress from the 5 th week of age as indicated by elevated levels of nuclear and mitochondrial 8-oxo-dG contents and TBARS. Also, GSH level showed depletion with age and the activity of glutathione reductase was lower in the β-cell and hepatic tissues of the offspring of diabetic mothers. The prenatal shift of redox status persists postnatal and exaggerates with age which may explain the significant induction of the apoptotic pathway in the pancreatic β-cell. Conclusion: Maternal diabetes can crucially affect the redox status in fetal tissues prenatally and these effects can persist postnatal which may play an important role in the programming of the metabolic state of the offspring. Postnatal diet play im-M. A. Kamel et al. 112 portant role in accelerating development of metabolic derangements and aggravates oxidative stress in the tissues of F1 offspring.

Gestational Diabetes Triggers Oxidative Stress in Hippocampus and Cerebral Cortex and Cognitive Behavior Modifications in Rat Offspring: Age- and Sex-Dependent Effects

“…The antioxidant system was disturbed in male and female GD offspring in the cerebral cortex and hippocampus at the juvenile age, which remained into adulthood. Oxidative stress resulting from a hyperglycemic intrauterine milieu increased the oxidative damage and alteration in the antioxidant defense during fetal [18] and neonatal [17] stages in the peripheric organs (the liver, kidney, and pancreas). Our results showed for the first time that these changes during the fetal stage remain into adulthood and specifically in the cerebral cortex and hippocampus.…”

“…Several studies have indicated that rats with GD and their offspring are exposed to oxidative stress, reporting increased biomarkers of oxidative stress in the liver, muscle, pancreatic cells, and brain [17,18]. In the brain, oxidative stress is involved in the neuroinflammatory state and excitotoxicity, two main causes of neural death [19].…”

Maternal diabetes impairs oxidative and inflammatory response in murine placenta

“…Diabetes mellitus during pregnancy affects the developmental milieu, jeopardizes the normal fetal development and increases the risk of various adult onset morbidities (Calkins and Devaskar 2011 ). We have previously demonstrated that diabetes during pregnancy increases oxidative stress in various fetal tissues including placenta (Kamel et al 2014 ). However, the effect of maternal diabetes on placental inflammation, vascular and oxidative stress markers specifically, was not studied thoroughly.…”

In-utero Exposure to Maternal Diabetes Increase the Risk of Vascular Diseases in the F1 Offspring in Rats

“…There are different approaches that could explain the enhanced level of NOx associated with increased other risk factors of vascular diseases; dyslipidemia and insulin resistance. Previously we reported an age dependent exaggeration of ROS production and oxidative stress in the offspring of diabetic mothers [38] this oxidative state may be the cause of the induction effect of hydrogen peroxide on the expression of eNOS at transcriptional and post-transcriptional level generating high level of NOx [39]. The resulting NO from highly expressed eNOS is degraded by reaction with (O 2 ) -to form peroxynitrite; a potent oxidizing agent that oxidize tetrahydrobiopterin (BH 4 ); a critical cofactor for NO synthesis by NOS.…”